Chronic kidney disease (CKD) affects over 26 million Americans. Agents that can directly halt the progression of CKD at the cellular and molecular level are much needed but lacking. The common pathway of CKD is renal fibrosis. Fibroblasts are key effectors of fibrosis by mediating aberrant remodeling of extracellular matrix (ECM). The epithelium-restricted v integrin, v6 directly activates latent TGF which in turn regulates fibroblast activity. Until recently much less was known about renal fibroblast v integrins. Our laboratory deleted all v integrins from activated myofibroblasts and found that these mice were dramatically protected from renal fibrosis following unilateral ureteral obstruction (UUO), an established model of tubulointerstitial fibrosis. Integrins are a family of transmemebrane cell-matrix receptors consisting of a and a subunit. In contrast to v6 whose expression is restricted to the epithelium, the other four v integrins, v1, v3, v5 and v8 can be expressed in fibroblasts. All can bind and/or activate TGF, a central fibrogenic factor, in vitro. Moreover, v integrins have been shown to work synergistically with growth factor receptors to initiate common downstream signaling pathways to regulate cell growth. The goal of this research is to determine which v integrins are expressed on pathologic renal myofibroblasts and how one or more of these integrins modulates the behavior of myofibroblasts to cause renal fibrosis. We will examine 3 interrelated candidate mechanisms - direct activation of latent TGF, enhancement of fibroblast proliferation and/or enhancement of differentiation into pathologic myofibroblasts. We will determine whether any of these effects of integrin signaling are regulated by its association with growth factor receptors. We also seek to identify which specific v integrin(s) contributes to the renal protective effects we saw in conditional v null mice. Global genetic deletion of 3 and 5 or fibroblast specific 8 deletion did not protect mice from liver fibrosis, suggesting that in that model either multiple fibroblast v integrins contribute or fibrosis depends on v1. Until now it was not possible to study the in vivo role of v1 since mice lacking 1 on myofibroblasts do not survive. To address this problem we have recently developed a highly potent and specific small molecule inhibitor of v1. We will take advantage of this novel compound as well as lines of mice that have already been generated in the laboratory to determine the identity of the critical v integrins that contribute to renal fibrosisin vivo. In summary, through this study, we will identify specific fibroblast v integrins and their signaling pathways essential for renal fibroblast activation. The experience and track record I gain from these studies, together with planned coursework and participation in external training programs should provide me with the skill set required to launch a successful academic career as a nephrology physician-scientist.